New grant seeks to parse how the variegated nature of human breast cancer tumors helps cancer cells resist treatment

A breast cancer tumor depicted in this multiphoton micrograph from a live mouse. Experimental animal models used to develop therapies do not capture the greater diversity or heterogeneity of human tumors
A breast cancer tumor depicted in this multiphoton micrograph from a live mouse. Experimental animal models used to develop therapies do not capture the greater diversity or heterogeneity of human tumors. Source: Joseph Szulczewski, NCI

The National Cancer Institute (NCI) has awarded a 5-year, $2.7 million grant to researchers at Sanford Burnham Prebys to investigate and elucidate the underlying cellular mechanisms that drive the most common form of breast cancer.

Specifically, how malignant cells with different kinds of mutations and genetics in estrogen receptor-positive (ER+) breast cancer are able to communicate with each other in the same tumor. Such diversity, or heterogeneity boosts their ability to resist treatment.

“One of the main reasons for therapeutic resistance in the clinic is that we use homogeneous experimental models to develop therapies, while in real world settings, there is a lot of heterogeneity within a cancer,” says principal investigator Svasti Haricharan, Ph.D., assistant professor and co-director of the Cancer Genome and Epigenetics Program.

Svasti Haricharan, Ph.D.

“Effectively treating cancer in a real patient is invariably more complex, subject to many more variables, than treating it in an animal model. It’s not simply a matter of solving a single jigsaw puzzle. It’s solving a bunch of different puzzles mixed together, each bunch unique to that patient.”

There are almost 300,000 new cases of invasive breast cancer diagnosed in women each year in the U.S. Primary ER+ breast cancer is the most common form, with a new diagnosis every 19 seconds.

ER+ breast cancer means that cancer cells in this subtype possess receptors that allow them to use the hormone estrogen to grow. The prevailing view is that estrogen acts as a catalyst for cancer growth because it stimulates cell division and tissue proliferation, and increases the risk for cancer-causing mutations. Some research suggests that estrogen plays an even more direct role by inducing genomic rearrangements leading to cancer.

ER+ breast cancer and progesterone receptor-positive (PR+) breast cancer comprise the so-called hormone receptor-positive (HR+) cancers, which account for two-thirds of all breast cancer cases in the United States. The vast majority, however, are specifically ER+: 67% to 80% in women, and 90% in men, according to the NCI.

In roughly 12% of ER+ patients, their breast cancer tumors entirely lack a protein called MLH1, whose functions include both recognizing and repairing DNA mismatched during replication and recombination and acting as a tumor suppressor.

In their previous work, Haricharan and colleagues have shown that MLH1 loss in ER+ breast cancer cells activates HER2, a protein that promotes cancer cell growth and makes them more resistant to standard endocrine chemotherapy, with patients more likely to suffer recurrence and relapse.

“ER+ breast cancer patients have high 5-year survival rates, but therapeutic resistance is common—their cancer comes back—and death occurs in about 40% of patients,” says Haricharan. “To prevent these deaths, we need to better understand the mechanisms and reasons why endocrine therapy becomes ineffective, and how cancer cells learn to resist it.”

In the newly funded NCI study, Haricharan’s lab will test the hypothesis that MLH1 loss in ER+ breast cancer induces secretion of HER ligands (molecules that bind to other molecules) and whether higher levels of HER ligands spurs therapeutic resistance. They will also investigate whether other cellular processes are impacted, such as DNA damage repair.

“Finding answers to these basic cancer biology questions has enormous real-word implications,” says Haricharan. “Our results may point the way to new therapies that will help the more than 25,000 women diagnosed each year with ER+ breast cancer characterized by MLH1 loss.”

In recent published research, Haricharan and colleagues have described how certain genetic mutations in breast cancer dictate different patient outcomes—not based on age—and why Black women experience higher breast cancer mortality than other demographic groups.

The grant is titled, “Regulation of the tumor microenvironment by DNA damage repair proteins" (R37 CA270362-01A1)

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